Tobacco use exacts an enormous toll on the health of America, with prevalence stalled at about 20% of all adults. Further reductions in smoking prevalence are impeded by several factors: (1) slow progress in the development of more effective cessation interventions;(2) low utilization of evidence-based interventions;and (3) ineffective use of interventions. The primary objective of the proposed Center is to establish a multidisciplinary laboratory designed to yield a comprehensive (individual to systems-level) smoking cessation intervention. This NIDA Center of Excellence application includes three research projects supported by four cores that together will produce a translatable, cost-effective, and clinically effective smoking cessation intervention package. The overall methodological approach is guided by the principles of intervention optimization. Project 1 will test multiple, evidence-based intervention components, administered at different phases of the cessation attempt, to identify the combination of components that produces optimal smoking cessation success. Project 2 will test two different types of clinician interventions that are prompted by the electronic medical record and designed to increase smokers'use of evidence-based cessation interventions. Project 3 will test three different types of interventions designed to increase smokers'effective use of cessation medication. In support of the research projects, the Center will create four cores: Administrative, Intervention Optimization, Methods, and Mentoring, Education, and Dissemination. These will provide the administrative, scientific, educational, and operational support needed to ensure the success of the research projects and the Center as a whole. Overall, this proposed Center of Excellence is designed to demonstrate the value of innovative, mutidisciplinary research strategies in producing optimal cessation packages;these strategies can be applied to diverse problems in health and drug abuse. The overarching goal of this Center of Excellence application is to reduce the prevalence of tobacco use in the United States, and the resulting burden of illness, death, and cost.